The large-scale Prostate Cancer Prevention Trial (PCPT) (N = 18,882 randomized men) of the 5a-reductase (SRD5A2) inhibitor finasteride (versus placebo) found that inhibiting SRD5A2 from converting testosterone into dihydrotestosterone reduced total prostate cancer risk by 25%, but also increased the risk of high-grade cancer. Although androgens appear to play an important role in prostate cancer, androgen levels decrease while estrogen levels remain constant or even increase as men age, resulting in as much as a 40% higher estrogen-to-androgen ratio. Metaplastic growth of the prostate has been produced by estrogens combined with a constant level of androgens, but estrogens alone inhibited prostate cell growth in vitro. Two estrogen receptors, ESR-a (ESR1) and ESR-3 (ESR2), are present in the human prostate and are the principal mediators of estrogen actions in prostatic stroma and epithelia. Using the comprehensive data and biospecimens of the PCPT, the present study is designed to evaluate the potential association of estrogen metabolism and its action in the prostate with high-grade prostate cancer in the PCPT. Our overall hypothesis is that increased serum androstenedione, estradiol and estrone and variations in genes that metabolize estrogens are associated with the finasteride-associated risk of high-grade prostate cancer. We will evaluate serum androstenedione, estrone and estradiol and the estrogen metabolizing genes CYP19 (aromatase), which converts testosterone and androstenedione into estrogens; 17-beta-hydroxysteroid dehydrogenase II (HSD17B2), which catalyzes the interconversion of estradiol and estrone; and the estrogen receptors (ESR1 and ESR2), which mediate estrogen action in the prostate. We propose nested case-control studies within the placebo and finasteride arms of the PCPT cohort (430 high-grade and 430 low-grade prostate cancer cases and 430 cancer-free controls [negative biopsy at the end of the PCPT]) to assess (a) whether serum concentrations of androstenedione, estradiol and estrone are associated with the risk of high-grade (Gleason score >7) prostate cancer and (b) whether specific polymorphisms in CYP19, HSD17B2, ESR1, and ESR2 affected the risk of high-grade prostate cancer in the PCPT, These studies will provide valuable new data elucidating the role of androstenedione and estrogens in finasteride-associated high-grade prostate cancer and elucidating the risk-benefit profile of current and potential future uses of finasteride. [unreadable] [unreadable] [unreadable]